Alpha, omega-di-substituted alkanes



atent 2,798,094 Patented July 2, 1957 ALPHA, GMEGA-DI-SUBSTITUTEDALKANES No Drawing. Continuation of applicationv Serial No.

344,960, March 26, H53. This application September 19 13, 1956, SerialNo, 609,558

7 Claims. (Cl. 260-5703) This invention relates to substituted diaminesand more extending media are useful for veterinary and human ad-'ministration to bring about the control or' cure of amebie infection.

Illustratively the new compounds can be prepared by condensing asuitably substituted 1,2-bis-(4-formylphe noXy) alkane with asubstituted aralkylamine to form an intermediate double Schiffs base,which is reduced with hydrogen catalyzed by palladium on charcoal, togive the corresponding secondary diamine. The substituted diamine isalkylated, as by treating with an aldehyde in the presence of an acid,followed by the addition of dilute alkali, to form the desireddi-tertiary amine. The following series of equations setting forth thepreparation of 1,2-ethanebis-(4'-oxy-3-methoxybenzyl-methyl-homoveratryl-arnine) will serve toindicate the course of the reacparticularly toa,w-bis-(oxybenzyl-alkylaaralkylamino) tions:

OHsO mam-Gomonmnfi 0 on-Q-oomomo CH0 1 CH! OH: 01130 O CH!CHaO-CH:CH2N=CH o emomoon=nomen-o OH:

CH3 CH3 Pd catalyst OHaO O CH: CHaO-CH2CH:NHCH2 0 011201120 GHNHCH:CH2 OCHI CH3 CH5 1 (C HOOOH OHsO OCH;

(3113 011a CH3O OCH:

OCHs

substituted alkanes, their acid addition salts and the processes fortheir preparation.

The bases of the compounds of the invention can be represented by theformula:

wherein each R1 represents hydrogen or a lower alkoxy radical, each R2represents hydrogen or a lower alkyl radical, each R3 represents a loweralkyl radical, each R4 represents hydrogen or a lower alkyl radical,each R5 represents hydrogen or a lower alkoxy radical, each R6represents hydrogen, a lower alkyl radical or a lower alkoxy radical, mrepresents an integer from 0 to 2 and n represents an integer from 2 to6. The bases are generally solids which are insoluble in water andsomewhat soluble in most organic solvents; the acid addition salts suchas the mineral acid salts of the bases are generally somewhat watersoluble, but as a rule are substantially insoluble in the typicalorganic solvents.

The new a,w-substituted alkanes and their acid solution salts areamebicides, and when administered orally or parenterally alone or incombination with pharmaceutical onto I As noted hereinabove, thea,w-substituted alkanes of the invention contain two basic nitrogenatoms which form acid addition salts with inorganic and organic acids.EX- amples of the inorganic acids suitable for the preparation of acidaddition salts are the common mineral acids, e. g. hydrochloric, nitric,sulfuric, and phosphoric acids; examples of organic acids capable offorming acid addition salts with the bases of the invention are acetic,propionic, tartaric, benzoic, salicylic, maleic and the like acids. Theacid addition salts of the novel bases of the invention are readilyprepared by methods known to the art, as for example, by interreactionof stoichiometrically equivalent amounts of the selected base and anacid in mutual inert solvent solution. The preferred acid addition saltsare the pharmaceutically useful salts, i. e., those salts which are notmaterially more toxic than the bases from which they are derived andwhich are suitable for incorporation into various pharmaceuticalpreparations useful for therapeutic application.

This application is acontinuation of our prior copend- 3 ing applicationfor patent, Serial No. 344,900, filed March 26, 1953, now abandoned.

The following examples illustrate the preparation and physicalproperties of representative substituted a,w-all anebis-(oxybenzyl-alkyl-aralkylamine) compounds of the in vention.

- Example 1 1,2-ethane bis-(4-oxybenzyl-methyl-4"-isopropylbenzyl-amine)dihydrochloride.

To a suspension of 18 g. of ethylene glycol-bis-(4-formylphenyl ether),prepared by the method of Neish, Rec. trav. chim. Pays-has, 66, 433,(1947), in 200 cc. of ethanol in a reduction flask were cautiously added2 g. of palladium on charcoal. The suspension was heated on a steam bathto about 60 C. and maintained at that temperature for about ten minutes.22.4 g. of p-isopropylbenzylamine were added to the reaction mixture andthe mixture, containing the'intermediate double Schiifs base, wasreduced with hydrogen in an Adams apparatus, with heating by means of aninfrared lamp. The reduction with hydrogen was completed within aboutthirty minutes, and the reaction mixture was filtered hot to remove thecatalyst. .On cooling, 1,2-ethanebis-(4'-oxybenzyl-4"-isopropylbenzylamine) crystallized and was removedby filtration, washed with alcohol and dried. Upon recrystallizationfrom ethanol, 1,2-ethane bis-(4-oxybenzyl-4- isopropylbenzylamine)melted at about 103-104 C.

Analysis.--Calculated for CsaHraNzOz: N, 4.97. Found: N, 4.99.

To a well stirred, cooled mixture of 20ml. of 37 percent aqueousformaldehyde solution and 45 ml. of 90 percent formic acid were added11.3 g. of 1,2-ethane bis- (4'-oxybenzyl-4"-isopropylbenzylamine) insmallport ions.

The solution was heated for one-half hour on the steam bath and finallyfor two hours at reflux temperature. The cooled solution was poured into200 ml. of ice water with stirring About cc. of iced 20 percent aqueoussodium hydroxide solution were added with stirring. The precipitate,comprising the 1,2-ethanebis-(4'-oxybenzylmethyl-4"-isopropylbenzylamine) formed in the reaction,was removed by filtration and dried in a desiccator over solid potassiumhydroxide. The dried material was recrystallized from a mixture of etherand petroleum ether.

1,2-ethane bis-(4' oxybenzyl-methyl-4"-isopropylbenzylamine) melts atabout 7576 C.

Analysis.'-Calculated for C40H52N2Qa: C, 81.01; H, 8.76; N, 4.72. Found:C, 81.01; H, 8.36; N, 4.79.

Dry hydrogen chloride gas was passed into a solution of 5 g. of1,2-ethane bis-(4-oxybenzyl-methyl-4"-isopropylbenzylamine) in ml. ofacetone until precipi- I tation was completed. The 1,2-ethanebis-(4'-oxybenzylmethyl-4"-isopropylbenzylamine) dihydrochloride formedwas removed by filtration, and upon recrystallization from boiling watermelted atabout 23 8- 240 C.

Analysis.-Calculated for C40H52N203'2HCl: C1, 10.66. Found: Cl, 10.20.

Example 2 1,2-ethane bis- (4-oxybenzyl-methyl-B-phenethylamine)dihydrochloride.

To a solution of 27 g. of 1,2-bis-(4'-formylphenoxy) ethane, preparedby'the method of Neish, Rec. trav. chim. Pays-has, 66, 433 (1947), in150 ml. of hot pyridine were added 24.2 g. of fi-phenethylamine. Thereaction mixture was placed in an Adams apparatus together with 3 g. of5 percent palladium on charcoal catalyst. After about 5 lbs. morehydrogen had been absorbed than required by theoretical considerations,the hot solution was filtered, the solvent was removed by evaporation invacuo and the residue was crystallized from ethanol. Afterrecrystallization from petroleum ether, 1,2-ethane bis-(4'-oxybenzyl-B-phenethylamine) thus prepared melted at about 109.5110.5 C.

Analysis.Calculated for CszHssNzOz: C, 80.00; H,

7.50; N, 5.83. Found: C, 80.20; H, 7.52; N, 5.92.

To a mixture of 20 m1. of 37 percent formalin and 45 ml. of percentformic acid were added 36 g. of 1,2- bis-(4'-oxybenzy1 13phenethylamine) under cooling. After the initial spontaneous reactionhad subsided, the mixture was refluxed for about two hours. The 1,2-bis-(4-oxybenzyl-methyl-fl-phenethylamine) formed in the reaction wasrecovered by pouring the reaction mixture into about 200 m1. of coldaqueous 5 percent sodium hydroxide. On recrystallization from petroleumether, the 1,2-ethane bis (4-oxybenzyl-methyl-fi-phenethylamine) meltedat about 70.5-71" C.

Analysis.Calculated for C34H40N2O2: C, 80.40; H, 7.87. Found: C, 80.41;H, 8.02.

Anhydrous hydrogen chloride was passed through a solution of 5 g. of1,2-ethane bis-(4-oxybenzyl-methyl- ,B-phenethylamine) dissolved in 50ml. of hot absolute ethanol. Sufficient ether was added to the solutionto bring about complete precipitation, and the solid salt was removed byfiltration. On recrystallization from a mixture of ethanol and ether,1,2-ethane bis-(4-oxybenzylmethyl-B-phenethylamine) dihydrochloridemelted at about 220-231 C. with decomposition.

Anaylsis.Calculated for C34H40N2Oz-2HCl: C, 70.23; H,7.29; Cl, 12.18; N,4.82. Found C, 70.25; H, 7.32; CI, 11.74; N, 4.96.

" Example 3 1,2-ethanebis-(3'-methoxy-4'-oxybenzyl-methyl-homoveratrylamine) dihydrochloride.

A mixture of 123.5 g. of ethylene bromide, 220 g. of vanillin, 500 ml.of water, and 500 ml. of methylcellosolve was brought to refluxing whilestirring, and a solution of 52.5 g. of sodium hydroxide in 250 m1. ofwater was added in the course of about one hour. Refluxing and stirringwere continued for about four hours, whereupon the reaction mixture wascooled; thereupon a precipitate of 1,2-bis-(4'-formyl-2'-methoxyphenoxy)ethane formed, and was filtered 01f, washed with water and dried. Uponrecrystallization from methylcellosolve, 1,2 bis (4-iicggnyT-methoxyphenoxy) ethane melted at about 186- A mixture of 16.5g. of 1,2-bis-(4'-formyl-2-methoxyphenoxy) ethane, 18.1 g. ofhomoveratrylamine and ml. of methylcellosolve was heated to dissolve thesolid. Three grams of 5 percent palladium on charcoal catalyst wereadded and the reaction mixture was placed in an Adams apparatus andhydrogenated while heating with an infrared lamp. After thehydrogenation was completed, the catalyst was removed from the reactionmixture by filtration. The solution was evaporated in vacuo and theresidue,comprising 1,2-ethane bis-(3'-methoxy-4'-oxybenzyl-veratrylamine) formed in the reaction, was recrystallizedfrom methanol and found to melt at about 113-115" C.

Analysis- -Calculated for C3sH4sN2Os: C, 69.09; H, 7.27. Found: C,69.16; H, 7.05.

A mixture of-15.0 g. of 37 percent formalin and 18.6 g. of 30 percentformic acid was cooled while 42.8 g. of 1,2-ethanebis-(3'-methoxy4'-oxybenzyl-veratrylamine) were added thereto. After theinitial spontaneous reaction had subsided, the reaction mixture wasbrought to boiling and maintained under refluxing for about three hours.The reaction mixture was poured into about 100 ml. of a cold aqueous 5percent sodium hydroxide solution. An oil comprising 1,2-ethanebis-(3'-methoxy-4'- oxybenzyl-methyl-homoveratrylamine) formed in thereaction separated as an oil. On standing overnight, the oilcrystallized. After two recrystallizations from methylcellosolve andethanol, the 1,2-ethane bis-(3'-methoxy-4'- oxybenzyl methylhomoveratrylamine) monohydrate melted at about 136-139 C.

Analysis.-Calculated for C40H52N208' lHzO: C, 69.76; H, 7.56. Found: C,69.55; H, 7.47.

Five grams of 1,2-ethanebis-(3'-methoxy-4'-oxybenzyl-methyl-homoveratrylamine) were suspended in50 ml. of ethanol and 10 ml. of water; and 5 m1. of concentratedhydrochloric acid were added thereto. Ether was, added to the reactionmixture until precipitation was completed. The 1,2-ethanebis-(3'-methoxy 4'-oxybenzylmethyl-homoveratrylamine) dihydrochloridemonohydrate thus formed was recrystallized from a mixture of alcohol,water and ether, and was found to melt at about 209-225 C. withdecomposition.

. Analysis.-Calculated for CaoHszNzOs-ZHCI- lHzO: C, 61.60; H, 6.98; Cl,9.09. Found: C, 61.83; H, 7.03; Cl, 8.90.

Example 4 1,4 butane bis (3 methoxy 4' oxybenzyl ethyl-'y-phenylpropylamine) dihydrochloride.

A mixture of 110 g. of tetramethylenedibromide, 170 g. of vanillin, 500ml. of methylcellosolve, and 400 ml. of water was brought to refluxingWhile stirring. A solution of 41 g. of sodium hydroxide in 225 ml. ofwater was added to the refluxing mixture over a period of about twentyminutes. Heating and refluxing were continued for five minutes and thenone liter of water was added to the reaction mixture. On chilling in anice bath, 1,4- bis-(4'-formyl-2-methoxyphenoxy) butane precipitated andwas removed by filtration. After recrystallization from methylcellosolvewith the addition of Water to the hot solution until incipientprecipitation, 1,4-bis-(4- formyl-Z-methoxy-phenoxy) butane melted at157.5- 159 C.

A mixture of 17.9 g. of 1,4-bis-(4'-formyl-2-methoxyphenoxy) butane, 9g. of ethylamine, 1 g. of percent palladium on charcoal catalyst and 100m1. of methylcellosolve was warmed for about one-half hour. The mixturewas then placed in an Adams apparatus and hydrogenated. Upon completionof hydrogenation and cooling, the catalyst Was removed by filtration andthe met'nylcellosolve was evaporated in vacuo. The residue, comprisingthe 1,4-butane his.-(3-methoxy-4'-oxybenzylethylamine) formed in thereaction, was recrystallized twice from a mixture of petroleum ether andbenzene, and was found to melt at 69.5-70 C.

AnaIyszls.-Calculated for C4oH52N2O4: N, 6.73.

Found: N, 6.98.

A mixture of 20 g. of 1,4-butane bis-(3'-methoxy-4'-oxybenzyl-ethylamine), 50 ml. of water, 50 ml. of methylcellosolve, 5.1g. of sodium carbonate, and 20.2 g. of 'yphenylpropylbromide wasrefluxed vigorously for about sixteen hours. The reaction mixture wasdiluted with one liter of Water, 25 ml. of a 50 percent aqueous sodiumhydroxide solution was added, and the 1,4-butane bis-(3'- methox-4'-oxybenzyl-ethyl- -phenylpropylarnine) formed in the reaction wasextracted with three successive 500 ml. portions of ether. The combinedether extracts were dried over anhydrous magnesium sulfate and dryhydrogen chloride gas was passed into the solution until precipitationwas complete. The precipitate was removed by filtration and crystallizedfrom a mixture of acetone and ether followed by a secondrecrystallization from alcohol. and ether. 1,4-butane bis-(3-methoxy-4'-oxybenzylethyl 'y phenylpropylamine) dihydrochloride hemihydrate thusprepared melted at about 132-135" C.

Analysis-Calculated for C42H5eN2O4-2HC1- l/2H2O: C. 68.6.);1-1, 8.10.Found: C, 68.83; H, 8.06.

To a suspension of 7.8 g. of 1,4-butanebis-(3'-methoxy-4-oxybenzyl-ethylphenylpropylamine) dihydrochloride in25 ml. of water was added 12 ml. of percent aqueous sodium hydroxide,with vigorous agitation. The mixture was extracted with three successive50 ml. portions of chloroform. The combined chloroform extracts weredried over anhydrous magnesium sulfate, and the solvent was removed byevaporation in vacuo. The residue was 1,4-butanebis-(3'-methoxy-4'-oxybenzylethyl-'y-phenylpropylamine) Example 51,2-ethane bis-(3'-methoxy-4-oxybenzyl methyl fiphenylisopropylamine)dihydrochloride.

A mixture of 4 g. of p-phenylisopropylamine, 5 g. ofl,4.-bis-(4-formyl-2-methoxy-phenoxy) ethane (prepared according to theprocedure of Example 3), and 150 ml. of methyl cellosolve was refluxedfor about four hours. The solvent was removed by evaporation in vacuo,and the oily residue consisting of the double Schifls base formed in thereaction was dissolved in about 50 ml. of ethanol and hydrogenated in anAdams apparatus, using 0.5 g. of 5 percent palladium on carbon catalystwhile heating by means of an infrared lamp. After cooling, the catalystwas removed by filtration and dry hydrogen chloride gas was bubbledthrough the alcohol solution until no further precipitation occurred.The solid was removed by filtration and recrystallized twice fromethanol.

LIZ-ethane bis-(3-methoxy-4-oxybenzyl-B-phenylisopropylamine)dihydrochloride thus prepared melted at about 248-250 C.

Analysis-Calculated for C3sH4sN2O4-2HCl: C, 67.16; H, 7.52. Found: C,66.86; H, 7.34.

The 1,2-ethane bis-(3'-methoxy-4'-oxybenzyl- 8-pheny1- isopropylamine)dihydrochloride was suspended in 100 ml. of water and a slight excess ofcold aqueous 10 percent sodium hydroxide was added to liberate the freebase. The aqueous mixture was extracted with three 100 ml. portions ofbenzene. The combined extracts were dried over anhydrous magnesiumsulfate and the benzene was removed by evaporation in vacuo. Theresidual 1,2- ethane bis-(3'-methoxy-4-oxybenzyl-B-phenylisopropylamine)base was used directly for further procedural steps.

To a cooled, stirred mixture of 10ml. of 37 percent aqueous formaldehydesolution and 20 ml. of percent formic acid were added 6 g. of 1,2-ethanebis-(3'-methoxy-4-oxybenzyl-fi-phenylisopropylamine) in small portions.The solution was heated for about one-half hour on a steam bath andfinally was refluxed for about two hours. The cooled solution was pouredinto ml. o ice water with stirring, and about 15 ml. of iced 20 percentaqueous sodium hydroxide were added. The resulting precipitate wasremoved by filtration, and consisted of 1,2-ethanebis-(3'-methoxy-4'-oxybenzyl-methyl- ,IJ-phenylisopropylamine).

The base was dissolved in about 50 ml. of acetone, and dry hydrogenchloride gas was bubbled into the acetone solution until no furtherprecipitation took place. The 1,2-ethane bis- (3-methoxy-4'-oxybenzyl-methyl-fl-phenylisopropylamine) dihydrochloridewhich formed was removed by filtration, and upon recrystallization fromboilin}? water melted at about 238--240 C.

Analysis.Calculated for CsaHszNzOa-ZHCI: 10.58. Found: Cl, 10.44.

Example 6 The procedure of Example 1 was followed, except thatbenzylamine was used instead of p-isopropylbenzylamine.

The 1,2-ethane bis-(4'-oxybenzyl-methyl-benzylamine) dihydrochloridethus prepared melted at about 213- Analysis.-Calculated forCs2H3sOzNz-2HCI: Cl, 12.81. Found: Cl, 13.00.

Example 7 The procedure of Example 1 was followed except thatp-Z-pentylbenzylamine was used instead of p-isopropylbenzylamine.

The dihydrochloride salt of 1,2-ethanebis-(4'-oxybenzyl-methyl-4-2-pentylbenzylamine) thus prepared melted atabout 211-212 C.

Analysis.-Calculated for C42HseN2O2-2HCl: Cl, 10.23. Found: Cl, 10.01.

Example 8 The method of Example 1 was repeated, using veratrylamineinstead of p-isopropylbenzylamine.

1,2-ethane bis-(4'-oxybenzyI-methyl-vetatryl m ne) dihydrochloride thusprepared melted at about 257-258 C. Analysis.-Calculated forC36H44N206'HC11 C, 64.22; H, 6.88; Cl, 10.59. Found: C, 63.95; H, 6.75;Cl, 10.62.

Example 9 The procedure of Example 3 was followed except thatveratryllamine was employed in place of homoveratrylamine.

The 1,2-ethane bis-(3-methoxy-4'-oxybenzyl-metl1ylveratrylamine)dihydrochloride formed in the process melted at about 230 C.

Analysis.Calculated for CasH4sN2Oa-2HCl: C, 62.24; H, 6.87; Cl, 9.67.Found: C, 62.33; H, 6.97; Cl, 9.67.

Example 10 The procedure of Example 1 was followed, except thatp-isopropylphenethylamine was used in place of p-isopropyl-benzylamine.

The 1,2 ethane bis-(4'-oxybenzyl-metl1yl-4"-isopropylphenethylamine)prepared by the process melted at about 75-76 C.

Analysis.-Calculated for C40H52N2O2: C, 81.01; H, 8.76; N, 4.72. Found:C, 81.01; H, 8.36; N, 4.79.

Example 11 The process of Example 3 was repeated, using benzylamineinstead of homoveratrylamine.

The dihydrochloride salt of 1,2-ethane bis-(3-methoxy- 4' oxybenzylmethyl benzylamine) melted at about 2ll2l2 C.

Analysis.-Calculated for C34H40N2O42 Cl, 11.55. Found: Cl, 11.67.

Example 12 Example 13 i The process of Example 2 was followed, exceptthat homoveratrylamine was employed instead of p-phenethylamine.

1,2-ethane bis-(4 oxybenzyl methyl homoveratrylamine) dihydrochloridethus prepared melted over a range of about 205-232 C.

Analysis.Calculated for C3sH4sN204-2HO12 N, 3.99. Found: N, 4.25.

Example 14 B-Phenethylamine was used in carrying out the process ofExample 3, in place of homoveratrylamine.

. 1,2 ethane his (3' methoxy 4'-oxybenzyl-methyl-flphenethylamine) thusprepared melted at about 6769 C. An'alysis.-Calculated for Gael-144N204:C, 76.00; H,

7.75. Found: C, 75.73; H, 7.79.

Example 15 Example 16 The process of Example 2 was repeated, using'y-phenylpropylamine in place of B-phenethylamine.

The dihydrochloride salt of 1,2-ethane bis-(4'-oxyhydrochloride thusprepared melted at about 184-185 8 benzyl-rnethyl-'y-phenylpropylamine)prepared in this manner melted at about 194-195 C.

Analysis.Calculated for CasH44NaO2'2HCl: Cl, 11.95. Found: Cl, 11.74.

Example 17 The process of Example 1 was repeated, except that propyleneglycol bis-(4-formylphenyl ether), prepared by the method of Neish, Rec.trav. chim. Pays-has 66, 433, (1947), and benzylamine were used insteadof ethylene glycol bis-(4-formylphenyl ether) andp-isopropylbenzylamine, respectively.

1,3-propane bis-(4-oxybenzyl-methyl-benzylamine) di-Analysz's.-Calculated for CasHssNzOz-ZHCI: 01, 12.50; N, 4.93. Found:Cl, 11.89; N, 5.00.

Example 18 The process of Example 2 was repeated, except that propyleneglycol bis-(4-formylphenyl ether) prepared by the method of Neish,supra, was used instead of l,3-bis-(4'- formylphenoxy) ethane.

The 1,3-propane bis-(4-oxybenzyl-methyl phenethylamine) dihydrochloridethus prepared melted at about ZOO-201 C.

Analysis.Calculated for Cs5H42N2O2-2HCl: Cl, 11.84. Found: Cl, 11.64.

Example 19 The procedure of Example 1 was repeated, except thatpropylene glycol bis-(4-formyl ether) was used instead of ethyleneglycol bis-(4-forrnylphenyl ether), and p-isopropyl-fl-phenethylaminewas used instead of p-isopropylbenzylamine.

The 1,3-propane bis-(4-oxybenzyl-methyl-4"-isopropyl-B-phenethylamine)dihydrochloride thus prepared melted at about 233-235 C.

Analysis.Calculated for C41H54NzOz-2HC1: Cl, 10.43. Found: Cl, 10.51.

Example 20 The process of Example 1 was carried out using propyleneglycol bis-(4-formylphenyl ether) and 'y-phenylpropylamine instead ofethylene glycol bis (4 formylphenyl ether) and p-isopropylbenzylamine,respectively.

1,3-propane bis-(4-oxybenzyl-methyl-'y-phenylpropylamine)dihydrochloride thus prepared melted at about 123-128 C.

' Analysis.-Calculated for CssHsoNzOr-ZHCl: C, 67.47; H, 8.01. Found: C,67.65; H, 8.31.

Example 21 A mixture of 103.5 g. of 1,3-dibromopropane, 170 g. ofvanillin, 500 ml. of methylcellosolve and 400 ml. of water was refluxedwhile stirring. A solution of 41 g. of sodium hydroxide in 225 ml. ofwater was added to the refluxing mixture over a period of about onehour. Heating and refluxing were continued for about four hours and thenthe reaction mixture was poured into about one liter of ice water. Thereaction mixture was chilled in an ice bath, and thel,3-bis-(4-formyl-2'- methoxy-phenoxy) propane which precipitated wasremoved by filtration. On recrystallization from alcoholwater solution,the l,3-bis-(4'-formyl 2 methoxy-phenoxy) propane melted at aboutl47.5-l48.5 C.

Analysis.Calculated for C19Hzo0s: C, 66.89; H, 5.81. Found: C, 66.12; H,5.49. The process of Example 3 was repeated, except that 1,3-bis-(4'-formyl 2' methoxy-phenoxy) propane was used instead of1,2-bis-(4'-formyl-2'-methoxy-phenoxy) ethane. 1,3-propanebis-(3-methoxy 4 oxybenzyl methylhomoveratrylamine) thus prepared meltedat about 127- 129 C. Analysis-Calculated for C41H54N2Oa: C, 70.05; H,7.74. Found: C, 70.33; H, 7.65. i

1,3-propane bis-(3-metho'xy 4' oxyb'enzyl methylhomoveratrylarnine)dihydrochloride sesquihydrate melted at about 164170 C.

Analysis.-Calculated for C41H54NzOa-2HCl-1%H2O: C, 61.34; H, 7.41.Found: C, 61.17; H, 7.22.

Example 22 The procedure of Example 2 was repeated, except that1,4-bis-(4'-forrnylphenoxy) butane, prepared according to the method ofNeish, Rec. trav. chirn. Pays-has, 66, 433, (1947), and benzylamine wereused instead of 1,2-bis- (4-formylphenoxy) ethane and fi-phenethylamine.

The 1,4-butane bis-(4'-oxybenzyl-methyl-benzylamine) thus preparedmelted at about 58-59 C.

Analysis.Calculated for C34H-10N202: N, Found: N, 5.44.

Example 23 Example 2 was repeated, except that1,4-bis.-(4.-formylphenoxy) butane was used instead of1,2-bis-(4'-formylphenoxy) ethane.

The dihydrochloride salt of 1,4 butane bis (4oxybenzyl-methyl-p-phenethylamine) prepared in this way melted at about221222 C.

Analysis.Calculated for CasHnNzOz-ZHCI: C, 70.93; H, 7.67; Cl, 11.63.Found: C, 70.67; H, 7.68; CI, 11.80.

Example 24 C40H52N2 O4 2HC1- 1C2H5 OH C, 67.85; H, 8.14. Found: C,67.96; H, 8.12.

Example 2.5

A mixture of 151 g. of pentamethylene dibromide, 220 g. of vanillin, 500ml. of water and 700 ml. of methylcellosolve was brought to refluxingtemperature and a solution of 52.5 g. of sodium hydroxide in 250 ml. ofwater was added over a period of about one hour while stirring.Refluxing and stirring were continued for an additional period of fourhours. The reaction mixture was poured into about two liters of icewater. The resulting precipitate of 1,5 -bis-(4-formyl 2 methoxyphenoxy)pentane was removed by filtration, washed with water and recrystallizedfrom absolute ethanol. l, -bis- (4'-formyl-2'-methoxy-phenoxy) pentanethus prepared melted at about 109110 C.

Analysis.-Calculated for C21H240e: C, 67.7; H, 6.45. Found: C, 67.5; H,6.34.

The procedure of Example 3 was repeated, using 1,5-bis-(4'-formyl-2'-methoxy-phenoxy) pentane instead of1,2-bis-(4'-formyl-2'-methoxy-phenoxy) ethane.

The dihydrochloride salt of 1,5 -pentane bis-(3-methoxy-4'-oxybenzyl-methyl-homoveratrylamine) thus prepared melted at about195-204 C.

Analysis.Calculated for C-raHesNzOa-ZHCI: C, 64.24; H, 7.52. Found: C,64.44; H, 7.50.

Example 26 1,2-ethane bis-(3'-methoxy-4roxybenzybmethyl homorveratrylamine) sulfate.

To a solution of 7.06 g. (0.01 mol) of 1,2-ethane bis- (3' methoxy 4oxybenzyl methyl homoveratrylamine), prepared according to the procedureof Example 3, in 50 ml. of cellosolve are added ml. of M/1 H2804. Thesolution is thoroughly stirred, and evaporated to dryness in vacuo.

The residue from evaporation is 1,2-ethane bis-(3- 10 methoxy 4oxybenzyl methyl homoveratrylarnine) sulfate.

Similarly, the nitric, acetic, propionic and benzoic acid addition saltsof 1,2-ethane bis-(3'-methoxy-4'-oxybenzylmethyl-homoveratrylamine) areprepared by the addition of stoichiometrically equivalent amounts ofnitric, acetic, propionic and benzoic acids to the solution of1,2-ethane bis (3 methoxy 4' oxybenzyl methyl homoveratrylamine)followed by evaporation of the solvent.

1,2-ethane bis-(4'-oxybenzyl methyl 4 isopropylbenzylamine) 1,2-ethanebis 4' oxybenzyl methyl-,6- phenethylamine) 1,4-butanebis-(3methoxy-4-oxybenzylethyl -phenylpropylamine) and 1,2-ethanebis-(3'methoxy-4'-oxybenzyl-methyl 13 phenyl-isopropylamine) aresubstituted for 1,2-ethanebis-(3'-methoxy-4-oxybenzylmethyl-homoveratrylamine) in the foregoingprocedures. The sulfate, dinitrate, diacetate, dipropionate, and diben:zoate salts of the named compounds, respectively, are obtained.

Example 27 1,2 ethane bis (4 oxy a ethylbenzyl methylveratrylamine) Amixture of g. (0.66 mol) of p-hydroxypropiophenone, 60 g. (0.33 mol) ofethylene dibromide, 230 m1. of methyl cellosolve and 230 ml. of waterwas brought to boiling under reflux, while stirring. A solutioncontaining 242 g. of sodium hydroxide in ml. of water was slowly addedto the boiling mixture over a period of about one hour. Stirring andrefluxing were continued for about four hours, and the mixture wascooled, whereupon a precipitate of 1,2-ethane bis-(4'- oxypropiophenone)formed and was removed by filtration and washed with water. Afterrecrystallization from a mixture of cellosolve and absolute ethanol,1,2-ethane bis (4-oxypropiophenone) melted at about 132-134 C.

Analysis-Calculated for C20H2204: C, 73.60; H, 6.79. Found: C, 73.55; H,6.83.

To a stirred solution of 58 g. (0.1 mol) of 1,2-ethanebis-(4-oxypropiophenone) in a warmed mixture of 300 ml. of pyridine and300 ml. of ethanol were added 60 g. (0.85 mol) of hydroxylaminehydrochloride, and the mixture was boiled under reflux for about sixteenhours. The solvents were partially removed by evaporation under reducedpressure, and upon cooling, a crystalline precipitate of 1,2-ethane bis-(4-oxypropiophenone) dioxime was formed. After recrystallization from alarge volume of ethanol, the dioxime melted at about 181182 C.

Analysis.Calculated for C2oH24N2O4: N, Found: N, 7.58.

The 1,2-ethane bis-(4'-oxypropiophenone) dioxime prepared as describedhereinabove was dissolved in about 100 ml. of ethanol and about 5 g. ofRaney nickel catalyst were added thereto. The ethanol solution wassaturated with ammonia gas, and the dioxime was reduced with hydrogen at100-110 C. under 2,000 lbs/sq. in. pressure in a hydrogenationapparatus. The mixture was filtered hot to remove the catalyst, and oncooling, a crystalline precipitate formed and was removed by filtration.After recrystallization from ethanol, the 1,2-et'nanebis-.(4-oxy-a-ethylbenzylamine) thus prepared melted at about 79-80 C.

Analysis.-Calculated for Found: N, 9.08.

A solution of 15 g. of 1,2-ethane bis-(4'-oxy-a-ethylbenzylamine) and 17g. of veratraldehyde in about 200 ml. of dry toluene was boiled underreflux in an apparatus containing a water separator. After refluxing forabout five hours no more water separated and refluxing was continued fora further period of about twelve hours. The toluene was removed from thereaction mixture by evaporation in vacuo, and the residue wascrystallized from ethanol. On recrystallization from ethanol the doubleSchiifs base formed in the reaction melted at about 142-143 C.

, 2,798,094 l 1 12 Analysis-Calculated for CEBHMNZOG! C, 73.08; H, andtheir acid addition salts, said bases being represented 7.04. Found: C,72.94; H, 6.96. by the formula:

The double Schiifs base prepared as described hereinwherein R1 is amember of the group consisting of hyabove was dissolved in about 200 ml.of N-ethylmordrogen and lower alkoxy radicals, R2 is a member of thepholine and about 2 g. of 5 percent palladium on chargroup consisting ofhydrogen and lower alkyl radicals, coal catalyst were added. The mixturewas placed in R3 is a lower alkyl radical, R4 is a member of the groupan Adams apparatus and reduced with hydrogen. The consisting of hydrogenand lower alkyl radicals, R is catalyst was removed from the reactionmixture by filtraa member of the group consisting of hydrogen and lowertion, and the solvent was evaporated in vacuo. The resialkoxy radicals,Re is a member of the group consisting due was dissolved in about 50 ml.of hot ethanol, and of hydrogen, lower alkyl radicals and lower alkoxyradiupon cooling, a crystalline precipitate of 1,2-ethane biscals, m isan integer from 0 to 2, and n is an'integer(4'-oxy-u-ethylbenzy1-veratrylamine) was formed. After from 2 to 6.crystallization from a mixture of ether and petroleum 2. 1,2 ethane bis(4 oxybenzyl methyl 4" isoether to which a few drops of methanol hadbeen added, propyl-benzylamine), represented by the formula:

1,2-ethane bis-(4'-oxy-a-ethylbenzyl-veratrylamine) melted at about 8586C.

3. 1,2-ethane bis-(4'-oxybenzyl methyl ,8 phenethyl- 5 amine),represented by the formula:

Analysis.--Calculated for C3aH4aNaOe: C, 72.64; H, 7.70. Found: C,72.60; H, 7.77. homoveratrylamine), represented by the formula:

GHaO OCHa CHsO OCH:

O CH1 CH3 CH3 To a well stirred, cooled mixture of 2 .5 ml. of 37 5.1,4-butane bis-(3'-methoxy-4-oxybenzyl-ethy1-ypercent aqueousformaldehyde solution and 5 ml. of 90 phenylpropylamine), represented bythe formula:

(!)CHs OHaO 4 CzHa C2 5 percent formic acid were added 1.5 g. of1,2-ethane bis- 6. 1,2-ethane bis-(3'-meth0xy-4-oxybenzyl-methyl-B-(4-oxy-a-ethylbenzyl-veratrylamine) in small portions.phenylisopropylamine), represented by the formula:

OOH: (311;?

4. 1,2-ethane bis-(3' methoxy 4 oxybenzyl-methyl- CH3 CH3 CH3 Hz Thesolution was heated for about one-half hour on a steam bath and finallywas boiled under reflux for about two hours. After cooling, the reactionmixture was poured into about 25 ml. of ice water, with stirring.

About 4 cc. of iced 20 percent aqueous sodium hydroxide wherein R1 is amember of the group consisting of hydrosolution were added withstirring, and a precipitate gen and lower alkoxy radicals, R2 is amember of the formed. The precipitate was removed by filtration, groupconsisting of hydrogen and lower alkyl radicals, R4 washed with icewater and dried in a' desiccator over is a member of the groupconsisting of hydrogen and lower solid potassium hydroxide. alkylradicals, R5 is a member of the group consisting of The 1,2-ethanebis-(4'-oxy-a-ethylbenzyl-methyl-vera- 5 hydrogen and lower alkoxyradicals, R6 is a member of trylamine) thus prepared was crystallizedand recrystalthe group consisting of hydrogen, lower alkyl radicals andlized from ethanol, and melted at about 1lO111 C. lower alkoxy radicals,m is an integer from 0 to 2, and

Analysis.Calculated for C4oH52N20s: C, 73.14; H, n is an integer from 2to 6. 7.98. Found: C, 73.00; H, 8.09.

We claim: l. A member of the group consisting of organic bases 7. Amember of the group consisting of organic bases and their acid additionsalts, said bases being represented by the formula:

7 No references cited.

1. A MEMBER OF THE GROUP CONSISTING OF ORGANIC BASES AND THEIR ACIDADDITION SALTS, SAID BASES BEING REPRESENTED BY THE FORMULA: